Viral hepatitides are internationally recognized tough questions in therapeutics up to now. Also, they are a class of hepatitides that are the most common and harmful with serious infectivity. In general, viruses leading to hepatitis are mainly divided into five types, i.e., types A, B, C, D and E. Among them, hepatitis A and E viruses infect intestinally, and their contamination in water source or food may result in pandemic infection. But hepatitides A and E will neither develop into chronic hepatitis, nor induce hepatocirrhosis, and patients recovering from them will gain a lifelong immunity. Viral hepatitides B, C and D are transmitted through blood, and a few of patients are infected by close contact with patient's saliva, semen, milk or the like, such as the infection between couples or mother and infant. Among the viral hepatitides, more than 80% of the acute infection with hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV) will progress to be chronic, wherein about 20% of them may possibly develop into hepatocirrhosis if suffered from persistent infection, and about 1% to about 5% of them may turn into liver cancer.
China has a high morbidity of viral hepatitides, there are 120 millions of hepatitis B virus carriers in China, and it is estimated that economic loss directly caused by viral hepatitides is about 30 to 50 billion RMB each year. While hepatitis C has a tendency of global prevalence and is the leading cause for the end-stage liver diseases in Europe, America and Japan. According to the statistics of WHO, the global infection rate of HCV is about 3%, and thus it is estimated that about 170 millions people have been infected with HCV, and about 35 thousands new cases of hepatitis C develop each year. A nationwide seroepidemiological investigation in China showed that the ratio of a person having anti-HCV antibodies in a general population was 3.2%.
HBV and HCV belong to different viral genera respectively, although they both belong to the hepatitis virus and have a similar route of infection. HBV belongs to the hepadnaviridae family and is made of a partially double-stranded circular DNA, while HCV belongs to the flaviviridae family and is a positive-sense single-strand RNA virus. At present, clinical anti-HBV drugs are mainly nucleoside drugs, such as lamivudine, famciclovir, lobucavir, adefovir dipivoxiil, FTC (2′,3′-dideoxy-5-fluoro-3′-thiacytidine), FMAU (1-(2-fluoro-5-methyl-beta,L-arabinofuranosyl)uracil), FDDC (5-fluoro-2′,3′-dideoxycytidine) BMS 200475 (9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]guanine), enticavir and the like. Since HBV and HCV belong to different viral genera, the existing anti-HBV drugs can not be used for treating Hepatitis C. So far, no effective small molecule drugs for HCV can be used in clinic. Presently, the most effective therapeutic regimen for HCV is the combined administration of interferon and broad-spectrum antiviral agent, such as interferon and ribavirin. But such combined administration only has a sustainable curative effect of less than 40% with serious adverse effect.
Therefore, as, it is always a focus for domestic and foreign pharmaceutical scientists to explore and develop a drug for treatment of viral hepatitides.
International application No. PCT/CN2007/001861 (International Publication No. WO 2007/147336), which is a previous international patent application of the present applicant, discloses a class of heterocyclic non-nucleoside compounds and the anti-HBV bioactivity thereof, and the compounds are useful for treating viral hepatitis B. However, the subsequent research reveals that some of the compounds exhibit poor pharmacokinetic parameters, especially bioavailability. For example, the oral bioavailability of Compound W28F in male rats (10 mg/kg) is only 2.80%. Thereby, there is an urgent demand to further modify the compounds so as to improve their bioavailability while maintaining their strong antiviral activity.
The present applicant incorporated a hydroxyl, a halogen atom or a double bond into the side chain at 5-site of thiazole ring of the 2′,2-bisthiazole non-nucleoside compounds among the above compounds based on the original structure. The obtained compounds not only retain the same anti-HBV bioactivity as the original ones, but also show effectively improved bioavailability. Extensive research reveals that, besides the anti-HBV bioactivity, such novel 2′,2-bisthiazole non-nucleoside compounds have an anti-HCV bioactivity.